Abnormalities in the development of the cerebral cortex can lead to a range of distinct neurodevelopmental disorders, including autism and Asperger's syndrome. Fresh insights into the dysregulation of cortical development associated with complex polygenetic disorders such as autism can be gained from studies on simpler monogenetic disorders that also are rooted in abnormal development of the cerebral cortex. One such disorder is bilateral frontoparietal polymicrogyria (BFPP), a condition in which patients exhibit disordered cortical connectivity resulting in profound cognitive abnormalities. BFPP is an autosomal recessive syndrome that results from mutations in the orphan receptor GPR56, which is a member of the poorly-understood adhesion family of G protein-coupled receptors. GPR56 possesses an extremely large extracellular amino-terminus (NT) that has homology to adhesion proteins and has been shown to be cleaved during receptor processing but yet remain associated with the seven-transmembrane (7TM) region of the receptor. However, the fundamental mechanisms of the activation and regulation of GPR56 signaling are presently unknown. Our preliminary studies have shown that expression of wild-type GPR56 in heterologous cells results in strong activation of Rho and b-catenin/Tcf signaling, and that truncation of the large GPR56-NT results in a receptor that is trafficked efficiently to the plasma membrane but no longer activates the aforementioned signaling pathways. We hypothesize that interaction of the GPR56-NT with an adhesion partner promotes receptor signaling, and will explore this idea by elucidating the structural determinants of the GPR56-NT that control receptor activity. We furthermore hypothesize that GPR56 signaling is highly regulated by cytoplasmic kinases, arrestins and PDZ scaffolds, and will explore these possibilities using a combination of phosphorylation assays, imaging studies, co-immunoprecipitation experiments, and siRNA knockdown approaches in both transfected cells and cultured cortical neurons. Knowledge gained from these studies will provide fresh insights into the role of GPR56 in human disease and also into the fundamental mechanisms that regulate the development of the cerebral cortex. PUBLIC HEALTH RELEVANCE: Abnormalities in the development of the cerebral cortex can lead to a range of distinct neurodevelopmental disorders, including autism and Asperger's syndrome. To shed light on the factors that contribute to such diseases, we propose to study the fundamental properties of the orphan receptor GPR56, which is believed to play a key role in cortical development since mutations in GPR56 cause a rare genetic disorder in which the development of the cerebral cortex is grossly distorted. Knowledge gained from these studies focused on the normal function of GPR56 will provide fresh insights into the role of GPR56 in human disease and also into the fundamental mechanisms that regulate the development of the cerebral cortex.